A Phase I Study of Bortezomib in Combination With Standard 5-Fluorouracil and External-Beam Radiation Therapy for the Treatment of Locally Advanced or Metastatic Rectal Cancer

O’Neil, Bert H.; Raftery, Laura; Calvo, Benjamin F.; Chakravarthy, A. Bapsi; Ivanova, Anastasia; Myers, Michael O.; Kim, Hee Jin; Chan, Emily; Wise, Paul E.; Caskey, Laura S.; Bernard, Stephen A.; Sanoff, Hanna K.; Goldberg, Richard M.; Tepper, Joel E.

doi:10.3816/ccc.2010.n.017

Cited by 28 publications

(16 citation statements)

References 14 publications

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“…One alternative approach to sensitize tumor cells to chemoradiation involves inhibition of the ubiquitin proteosome system, which is commonly aberrant in cancer (70). Several agents targeting the ubiquitin proteosome are in various phases of development (e.g.…”

Section: Sensitizing To Chemoradiation By Alternative Strategiesmentioning

confidence: 99%

“…BRCA1, MDC1, Ku80) (72), there is currently no clear evidence that bortezomib affects DNA repair. Unfortunately, initial attempts to combine bortezomib with chemoradiation have produced increased toxicity with no apparent benefit in terms of tumor reduction (70). Toxicity associated with bortezomib may be related to the deleterious effects of broadly inhibiting ubiquitin-mediated protein degradation.…”

Section: Sensitizing To Chemoradiation By Alternative Strategiesmentioning

confidence: 99%

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Improving the Efficacy of Chemoradiation with Targeted Agents

et al. 2014

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Chemoradiation is the standard therapy for the majority of inoperable, locally advanced cancers. While there is a need to improve chemoradiation efficacy, normal tissue toxicity limits our ability to give additional chemotherapy or higher doses of radiation. Thus, there is excitement about the addition of molecularly targeted agents, which tend to be less toxic than chemotherapy, to chemoradiation regimens. Unfortunately, initial empiric attempts have not been successful. This review will focus on the evidence that supports rational combinations of targeted agents with chemoradiation, with an emphasis on agents that target the DNA damage response and radiation-induced membrane signaling.

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Section: Sensitizing To Chemoradiation By Alternative Strategiesmentioning

confidence: 99%

Section: Sensitizing To Chemoradiation By Alternative Strategiesmentioning

confidence: 99%

Improving the Efficacy of Chemoradiation with Targeted Agents

et al. 2014

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“…No DLTs were observed. O’Neil et al [19] performed a phase I study of 5-fluorouracil and bortezomib concurrent with RT for rectal cancer. Diarrhea was the dose limiting toxicity at the 1 mg/m 2 /dose level but NF- κB activation did not appear to be suppressed at that dose.…”

Section: Discussionmentioning

confidence: 99%

Concurrent whole brain radiotherapy and bortezomib for brain metastasis

et al. 2013

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BackgroundSurvival of patients with brain metastasis particularly from historically more radio-resistant malignancies remains dismal. A phase I study of concurrent bortezomib and whole brain radiotherapy was conducted to determine the tolerance and safety of this approach in patients with previously untreated brain metastasis.MethodsA phase I dose escalation study evaluated the safety of bortezomib (0.9, 1.1, 1.3, 1.5, and 1.7 mg/m2) given on days 1, 4, 8 and 11 of whole brain radiotherapy. Patients with confirmed brain metastasis were recruited for participation. The primary endpoint was the dose-limiting toxicity, defined as any ≥ grade 3 non-hematologic toxicity or grade ≥ 4 hematologic toxicity from the start of treatment to one month post irradiation. Time-to-Event Continual Reassessment Method (TITE-CRM) was used to determine dose escalation. A companion study of brain diffusion tensor imaging MRI was conducted on a subset of patients to assess changes in the brain that might predict delayed cognitive effects.ResultsTwenty-four patients were recruited and completed the planned therapy. Patients with melanoma accounted for 83% of all participants. The bortezomib dose was escalated as planned to the highest dose of 1.7 mg/m2/dose. No grade 4/5 toxicities related to treatment were observed. Two patients had grade 3 dose-limiting toxicities (hyponatremia and encephalopathy). A partial or minor response was observed in 38% of patients. Bortezomib showed greater demyelination in hippocampus-associated white matter structures on MRI one month after radiotherapy compared to patients not treated with bortezomib (increase in radial diffusivity +16.8% versus 4.8%; p = 0.0023).ConclusionsConcurrent bortezomib and whole brain irradiation for brain metastasis is well tolerated at one month follow-up, but MRI changes that have been shown to predict delayed cognitive function can be detected within one month of treatment.

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“…Even more disappointing conclusions were drawn from a study of bortezomib in combination with 5-fluorouracyl and radiotherapy for the treatment of locally advanced or metastatic rectal cancer. The authors concluded that the clinical applicability of the protocol is limited and that samples of the tumors did not show any evidence of NF-jB gene suppression (O'Neil et al 2010). In conclusion, despite the fact that bortezomib was approved for treatment of multiple myeloma and mantle-cell lymphoma, its common use for therapy of solid tumors is still under extensive clinical investigation.…”

Section: Proteasome Inhibitorsmentioning

confidence: 99%

Targeting NF-κB and HIF-1 Pathways for the Treatment of Cancer: Part I

Wilczyński

Duechler

Czyż

2011

Arch. Immunol. Ther. Exp.

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The process of chronic inflammation is a common link which connects different kinds of environmental pollutants and infections with tumorigenesis. Transcription factor NF-κB is a common final target for many inflammatory and cell proliferation pathways, independent of the source of stimuli (e.g., cytokines, growth factors, environmental carcinogens, radiation, hypoxia, bacteria, and viruses). Over-activation of NF-κB has been confirmed in many tumors, resulting in worse prognosis for patient survival. Therefore, inhibition of cellular pathways for NF-κB activation is nowadays considered as a promising anti-cancer therapy and is extensively studied in clinical trials, or even has been adopted as an approved therapy in some kinds of cancer.

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A Phase I Study of Bortezomib in Combination With Standard 5-Fluorouracil and External-Beam Radiation Therapy for the Treatment of Locally Advanced or Metastatic Rectal Cancer

Cited by 28 publications

References 14 publications

Improving the Efficacy of Chemoradiation with Targeted Agents

Improving the Efficacy of Chemoradiation with Targeted Agents

Concurrent whole brain radiotherapy and bortezomib for brain metastasis

Targeting NF-κB and HIF-1 Pathways for the Treatment of Cancer: Part I

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